Journal Article

Comprehensive characterization of protein–protein interactions perturbed by disease mutations

Castrillon, Jessica A., Keri, Ruth A., Eng, Charis, Huang, Jin, Cheng, Feixiong, Lu, Weiqiang, Lightstone, Felice C., Zhou, Yadi, Fang, Jiansong, Lathia, Justin D., Vidal, Marc, Wang, Ruisheng, Wang, Yang, Ma, Jing, Zhao, Junfei, Hou, Yuan, Martin, William R., Yue, Hong, Hao, Tong, Liu, Zehui, Antman, Elliott Marshall, Rabadan, Raul, Hill, David E., Loscalzo, Joseph

2021

Overview

Technological and computational advances in genomics and interactomics have made it possible to identify how disease mutations perturb protein–protein interaction (PPI) networks within human cells. Here, we show that disease-associated germline variants are significantly enriched in sequences encoding PPI interfaces compared to variants identified in healthy participants from the projects 1000 Genomes and ExAC. Somatic missense mutations are also significantly enriched in PPI interfaces compared to noninterfaces in 10,861 tumor exomes. We computationally identified 470 putative oncoPPIs in a pan-cancer analysis and demonstrate that oncoPPIs are highly correlated with patient survival and drug resistance/sensitivity. We experimentally validate the network effects of 13 oncoPPIs using a systematic binary interaction assay, and also demonstrate the functional consequences of two of these on tumor cell growth. In summary, this human interactome network framework provides a powerful tool for prioritization of alleles with PPI-perturbing mutations to inform pathobiological mechanism- and genotype-based therapeutic discovery. Human disease mutations affect protein–protein interfaces in a three-dimensional structurally resolved interaction network. Predicted oncoPPIs in cancer correlate with survival and drug sensitivity, and affect growth in vitro, supporting their relevance to disease pathogenesis.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 101/47 / 45/111 / 631/114 / 631/208 / 631/535 / 631/553 / 82/81 / Agriculture / Amino acids / Animal Genetics and Genomics / Arachidonate 5-Lipoxygenase - genetics / Arachidonate 5-Lipoxygenase - metabolism / Arginine - genetics / Arginine - metabolism / BASIC BIOLOGICAL SCIENCES / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer Research / Computational Biology - methods / Computer applications / Disease / Disease - genetics / Drug resistance / Gene Function / Genome, Human / Genomes / Genomics / Genotypes / Histones - genetics / Histones - metabolism / Human Genetics / Humans / Interfaces / Missense mutation / Mutation / Neoplasms - genetics / Pharmacogenomic Testing / Proprotein Convertase 9 - genetics / Proprotein Convertase 9 - metabolism / Protein interaction / Protein Interaction Maps - genetics / Proteins / Receptors, LDL - genetics / Receptors, LDL - metabolism / Reproducibility of Results / rho Guanine Nucleotide Dissociation Inhibitor alpha - genetics / rho Guanine Nucleotide Dissociation Inhibitor alpha - metabolism / rhoA GTP-Binding Protein - genetics / rhoA GTP-Binding Protein - metabolism / Serine - genetics / Serine - metabolism / Tumors